The incidence of obesity and it's related disorders are reaching epidemic proportions, making it imperative that we develop effective treatments immediately. Obesity develops when energy input (e.g. food intake) exceeds energy output (e.g. exercise), and one key regulator of energy balance is the fat-derived hormone leptin, which acts primarily in the brain. We will study a key regulator of leptin action, PTP1B, in specific areas of the brain, to discern it's potential involvement in obesity. Leptin undergoes negative regulation by the ubiquitously expressed protein tyrosine phosphatase PTP1B, suggesting that PTP1B may be a useful target for drug therapy in leptin resistance. We have previously shown that the effects of PTP1B on leptin signaling occur primarily in the brain, and largely in the hypothalamus. It is still unclear; however, which nuclei in the brain are critical for the effects of PTP1B on leptin sensitivity. We will examine the role of PTP1B in leptin pathway regulation in the arcuate nucleus (POMC neurons) and the ventral medial hypothalamus (SF-1 neurons), both areas shown to play key roles in energy balance and obesity. Using Cre-loxP Recombinase methodology, we have mice with deletion of PTP1B protein specifically in POMC or SF-1 neurons. We will examine the role of PTP1B regulation in these neurons by looking at the effect of PTP1B deletion on body weight, body composition using dual energy x-ray absorptiometry, energy expenditure using indirect calorimetry, and glucose metabolism (Aim #1). We hypothesize that if PTP1B plays a critical role in leptin signaling regulation in these neurons, mice without the protein will have decreased body weight, reduced adiposity, enhanced energy expenditure and improved glucose metabolism, all consistent with enhanced leptin sensitivity. We predict these effects to be more pronounced with diet-induced obesity, and thus leptin resistance. Therefore we will study these mice both on normal and high fat diet. Next, we will look at the potential molecular mechanisms responsible for the effects of PTP1B deletion in POMC and SF-1 neurons on energy balance by examining the leptin signaling pathway in control vs. POMC and SF1-PTP1B -/- mice (Aim #2). Specifically, we will look at the ability of exogenous leptin to suppress food intake, induce phosphorylation of key enzymes in the leptin pathway such as STATS and AMPK, and the ability of leptin to induce expression of important neuropeptides for energy regulation. We hypothesize that PTP1B plays a role in leptin resistance in POMC and SF-1 neurons, thus enhancing leptin signaling upon it's inhibition. By attempting to determine the specific neurons critical in these pathways, we hope to bring research closer to developing effective treatments for obesity with minimal side effects. [unreadable] [unreadable] [unreadable]